Identification of pyrazolotriazinones as potential agents for hyperuricemia treatment by using in vitro and in silico studies

M. LOURDES SCIÚ; JUAN P. COLOMER; E. LAURA MOYANO; JORGE CANTERO; M. GABRIELA ORTEGA; M. DANIELA SANTI; MARGOT PAULINO-ZUNINI

SN Applied Sciences

Springer Nature

Año: 2020 vol. 2 p. 1 - 14

Heterocyclic compounds structurally related to purine bases have been described as anticonvulsants, antifungal, antiviral,anticancer, enzyme inhibitors, among others. In this work, pyrazolo[3,4-d][1-3]triazin-4-ones (2) and pyrazolo[4,3-d][1-3]triazin-4-ones (3) derivatives were evaluated as xanthine oxidase (XO) inhibitors. Compounds 3 showed the best activitywith IC50values range of 0.9?2.9 μM. While the inhibition performance of pyrazolotriazinones was not more active thanreference inhibitor allopurinol (IC50 = 0.247 ± 0.004) μM, these nuclei provide a platform for new and more potent XOinhibitors. Accordingly, molecular modeling methods were carried out to understand the compounds-enzyme bindingmode. First, we have performed a qualitative SAR study using the MOE? SAR tool. This study showed three commonscaffolds and the most active was identified. These results are certainly valuable and will be taken into account in futuresynthesis of structurally related compounds. Furthermore, QSAR 2D and 3D studies were performed and structuralrequirements for the activity are reported. The obtained results led us to present the structural improvements for therational design and synthesis of new pyrazolotriazinone derivatives with greater xanthine oxidase inhibitory activitythan allopurinol.